Abstract 17361: Dose-dependent Differential Impact of Estrogen Replacement on Abdominal Aortic Aneurysm Formation in a Murine Model
Backgrounds: Women have a lower incidence of abdominal aortic aneurysm (AAA) than men, but lose this gender advantage after menopause, implying favorable effects of estrogen. However, the effects of hormone replacement therapy (HRT) on cardiovascular disease remain controversial. We assessed whether dosage affects the impact of estrogen replacement on AAA formation.
Methods: Female C57/BL6 mice (8-weeks-old) underwent ovariectomy (OVX) with or without osmotic pump implantation containing 17β-estradiol (low-dose; 20μ g/kg/day (LE2), high-dose; 400μ g/kg/day (HE2)). Control mice were subjected to a sham surgery. Four weeks later, aortic porcine pancreatic elastase perfusion was performed to induce experimental AAA.
Results: We have previously shown that females show decreased AAA formation vs.males in this experimental murine AAA model. In contrast, OVX mice developed larger AAAs with more macrophage infiltration than control mice by 14 days (Figure). LE2 treatment completely suppressed the exacerbation caused by OVX, whereas these protective effects were diminished in HE2 mice (Figure). QRT-PCR demonstrated that gene expression of inflammatory cytokines, TNF-α, MCP-1 and CCL4, as well as adhesion molecule, VCAM-1 in AAAs were upregulated at day7 in OVX mice compared to control mice; treatment with LE2 abrogated these changes in gene expression. However, HE2 had little effect on TNF-α, MCP-1 and CCL4. In additon, thioglycolate-elicited peritoneal macrophages from HE2 mice showed highly significant upregulation of TNF-α, TLR4 and MyD88 expression compared with those from LE2 mice.
Conclusion: Previous studies have shown beneficial effects of estrogen on vascular inflammation, but some reports suggest that estrogen may promote macrophage activation. The dose differential impact of estrogen in the present study may provide novel insight into the contradicting outcome of HRT on cardiovascular disease.
- © 2012 by American Heart Association, Inc.